Ideal physiological functioning requires an appropriate balance between nerve cell excitation and inhibition. Therefore, the identification of compounds, and methods of utilizing these compounds, to alter this balance, is of great interest and value.
It is well known that nociceptive pain and neuropathic pain are caused by different mechanisms, and therefore respond to different treatment modalities. Nociceptive pain is mediated by receptors which are located in skin, bone, connective tissue, muscle and viscera. These receptors typically respond to noxious chemical, thermal and mechanical stimuli producing pain that is typically described as sharp, aching, throbbing, or gnawing. In contrast, neuropathic pain is produced by damage to, or pathological changes in, the peripheral or central nervous systems, typically producing pain that is described as “burning”, “electric”, “tingling”, and “shooting” in nature. In fact, neuropathic pain is most often diagnosed based on the symptoms, such that any pain that is characterized by burning sensations and/or shooting pain and/or numbness and/or tingling and/or allodynia is typically considered neuropathic. Other characteristics of neuropathic pain include hyperpathia (greatly exaggerated pain sensation to stimuli), hyperesthesia (an increased sensitivity to normal stimulation), dysesthesia (unpleasant abnormal sensations as if damage is being done when this is not the case), and paresthesia (an abnormal sensation, such as “pins and needles”, whether spontaneous or evoked).
Nociceptive pain usually responds to opioids and non-steroidal anti-inflammatories (NSAIDS), whereas the success of treating neuropathic pain with these approaches has been limited. Conversely, agents employed to treat neuropathic pain, such as gabapentin, have little or no effect on nociceptive pain.
Current conventional pharmacologic strategies for treating neuropathic pain follow a number of different approaches as outlined below:                Antiarrhythmics: Certain antiarrhythmics have sodium-blocking activity. Low-dose IV lidocaine is sometimes used for temporary pain relief from peripheral nervous system injuries, including diabetic neuropathy and postherpetic neuralgia. However, IV lidocaine therapy requires constant monitoring of the patient's ECG and blood pressure to decrease the risk for seizures and arrhythmias. (1)        Antidepressants: Both tricyclic antidepressants and serotonin reuptake inhibitors have been used to treat neuropathic pain. Numerous clinical trials demonstrate the safety and efficacy of TCAs when used to treat either diabetic neuropathy or postherpetic neuralgia, yet response rates have been low at approximately 33%. Amitriptyline was the first tricyclic used to treat neuropathy, and it is still widely prescribed. Amitriptyline has a high incidence of anticholinergic side effects, including delirium in elderly patients. TCAs also have proarrhythmic effects which limit their use in populations with abnormal EKG. Serotonin specific reuptake inhibitors (SSRIs) have demonstrated less consistent effects on neuropathic pain, relieving neuropathic pain in only one of seven patients. Serotonin noradrenaline reuptake inhibitors have fared slightly better with a response rate of one in every 4-5 neuropathic pain sufferers. (2)        Anticonvulsants: Carbamazepine, phenytoin, gabapentin and lamotrigine have all been used to treat neuropathic pain. Inhibition of sodium channel blocking activity by agents such as carbamazepine, phenytoin, and lamotrigine is the proposed mechanism. Studies have shown the anticonvulsant gabapentin to be effective in painful diabetic neuropathy, mixed neuropathies, and postherpetic neuralgia. The most common adverse effects of anticonvulsants in general are sedation and cerebellar symptoms (nystagmus, tremor and incoordination). The most common side effects associated with gabapentin are asthenia, headache, dizziness and somnolence, and in some cases polyneuropathy. Lamotrigine was no better than placebo when used to treat neuropathic pain other than trigeminal neuralgia. (3)        NSAIDS: NSAIDS are not generally recommended first-line agents for treating neuropathic pain. Relief of neuropathic pain with nonsteroidal anti-inflammatory drugs (NSAIDs) is variable. (4)        Opioids: Treatment of neuropathic pain has with opioids has been controversial. Opioids were thought to be ineffective for treating neuropathic pain, but may be somewhat effective for patients who have failed other modalities. Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain, while intermediate-term studies demonstrate significant efficacy of opioids over placebo. Reported adverse events of opioids are common and long-term efficacy, safety (including addiction potential), and effects on quality of life need to be further evaluated. Overall, neuropathic pain may be less responsive to opioids than other types of pain. (5)        Other Agents: Baclofen, which blocks both presynaptic and postsynaptic GABA B receptors, is used as a first-line agent to treat trigeminal neuralgia. The most common side effect is drowsiness, and there is concern about possible addictive effects. (6)        Ketamine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, has garnered increased interest for treating neuropathic pain. Ketamine has been shown to relieve the symptoms of postherpetic neuralgia. However, ketamine causes sedation, slowed reaction times and hallucinations with long-term use. For this reason, it not currently recommended for use in chronic non-malignant pain. (7)        Dextromethorphan is also an NMDA antagonist. It has been used with some success to decrease pain in patients with diabetic neuropathy, but has not benefited those with postherpetic neuralgia, post stroke pain, or peripheral neuropathies other than diabetic. (8)        Topical Agents: Topical agents offer the advantage of local relief without systemic toxicity. Transdermal clonidine has been used with mixed results to treat diabetic neuropathy. Capsaicin cream, which contains an extract of chili peppers, is sometimes used to treat neuropathic pain. It may act on unmyelinated primary afferent nerves by depleting substance P. Depletion requires repeated and consistent use of capsaicin, and patient compliance can be an issue due to the common side effect of an intense burning sensation that decreases with consistent use. Overall, relief with capsaicin cream in clinical trials of neuropathic pain has been inconsistent. (4) Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on transdermal ketamine demonstrate efficacy in neuropathic pain. (9) Geranium oil, a steam distillate of the geranium plant (Pelargonium spp) that is used in flavors and fragrances, is generally regarded as safe by the U.S. Food and Drug Administration. Topical application of geranium oil has been shown to relieve the pain of post-herpetic neuralgia in ⅔ subjects, with ¼ of subjects having a dramatic clinical response. (10)        
Overall, the efficacy of these pharmacological treatments is often limited by side effects at the doses required for analgesia, as well as in some cases long delays before the onset of analgesia, a substantial rate of non responsiveness to therapy, and a potential for addiction. In conclusion, neuropathic pain does not have an ideal or even a very good treatment at the present time. A new and novel non-toxic topical or oral preparation to treat neuropathic pain is therefore of great interest and has the potential to benefit a wide range of chronic pain sufferers.
Natural substances provide a rich diversity of chemical structures, many of which have shown efficacy as therapeutic agents. In terms of inhibition of nerve function, a variety of classes of naturally derived compounds has shown the ability to inhibit neuronal firing by various methods, including affects on nerve cell receptors and associated ion channels. For example, flavanoids, terpenes, terpenoids, ginsenosides, and a variety of other dietary and environmental compounds have been shown to influence nerve transmission rates. (17)
Borneol, for instance, is a bicyclic monoterpene present in the essential oils of a number of medicinal plants, and has been shown to have a “highly efficacious” modulating action on nerve cell receptors. (18) Interestingly, traditional herbs containing borneol, such as valerian officinalis, matricaria chamomilla, and lavandula officinalis, have been used as sedatives to relieve anxiety, restlessness, insomnia and as analgesics. No other terpene has been previously found to have effect on nerve cell transmission.
In fact, many plant derived essential oils have been reported to have beneficial analgesic and anti-inflammatory properties for the treatment of nociceptive pain. For example, a number of species of ginger (Zingiber spp.) have been shown to consisting of monoterpenes (phellandrene, camphene, cineole, citral, and borneol), sesquiterpenes (zingiberene, zingiberol, zingiberenol, β-bisabolene, sesquiphellandrene, and others), aldehydes and alcohols. (11) Menthol is a common and naturally occurring compound of botanical origin found in plants of the Mentha genus which has also been shown to possess analgesic properties with regard to nociceptive pain. (12) There has been, however, very little research into plant extracts for the treatment of neuropathic pain. One controlled trial of a Cannabis based extract given as an oromucosal spray (Sativex®, GW Pharmaceuticals, United Kingdom), however, did show benefit in centrally mediated neuropathic pain in 64 multiple sclerosis patients. (13)
Geranium oil has been used extensively in perfumery, as an insect repellent, and for other related purposes. For example, U.S. Pat. No. 4,940,583, Thompson, describes the use of geranium oil as a component in an animal repellent composition. U.S. Pat. No. 4,923,685, Forg et al., describes the use of geranium oil as part of a mouth wash composition. U.S. Pat. No. 4,579,677, Hooper et al., describes the use of geranium oil as a scenting agent in a bleaching composition. U.S. Pat. No. 4,311,617, Ansari et al., describes the use of geranium oil in perfumery compositions. United States Patent 5,260,313, Frome, entitled “Diagnosis and treatment of various neuralgias,” relates to a method of diagnosing and treating neuropathic pain syndromes with a composition of which Pelargonium graveolens Ait. oil is the principle therapeutic agent. This essential oil distillate is alternatively called geranium oil, bourbon, oil geranium reunion, and oil rose-geranium.
The use of an essential oil distillate geranium oil, however, as taught by Frome, employs a complex mixture of naturally derived compounds, some of which may be effective for neuropathic pain relief and some which may be ineffective or which may be irritating or toxic. For example, a number of constituents found in natural geranium oil are known irritants and thereby may cause skin rash when applied topically or even exacerbate pain. For instance a-pinene, a constituent of natural geranium oil, is considered irritating to the skin and exposure can cause rash, burning pain, headache, vomiting and even kidney damage. (15) B-phellandrene has known hypersensitizing effects which can cause contact dermatitis. (16) P-cymene, another component of natural geranium oil, is also considered a “primary skin irritant”, which can cause erythema upon contact and headache, nausea and vomiting if exposure is oral or inhaled. (17)
There remains a need for alternative therapies for inhibition of nerve cell transmission that do not suffer the drawbacks associated with existing pharmaceuticals, including essential oil distillates.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the presently claimed and disclosed invention(s). No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the presently claimed and disclosed invention(s).